Epothilones are macrolide compounds having utility in the pharmaceutical field. For example, Epothilones A and B are naturally-occurring compounds that can be isolated from certain microorganisms, having the structures:

Known epothilones exert microtubule-stabilizing effects similar to TAXOL® and therefore exhibit cytotoxic activity against rapidly proliferating cells, such as occur in cancer and other hyperproliferative cellular diseases (See Angew. Chem. Int. Ed. Engl., Vol. 35, No. 13/14, 1996 and D. M. Bollag, Exp. Opin. Invest. Drugs, 6(7): 867-873, 1997).
Since the introduction of epothilones into the art, many groups have been designing, synthesizing and testing analogs of the naturally occurring epothilones in an attempt to develop useful pharmaceuticals. (See, e.g., D. Schinzer et al. Angew. Chem. Int. Ed. Eng., 1997, 36, No. 3, 523-524; K. C. Nicolaou, et al., J. Amer. Chem. Soc., 1997, 119, 7974-7991; (K. C. Nicaloau et al., Angew. Chem. Int. Ed. Engl., 1996, 35, No. 20, 2399-2401; A. Balog et al., Angew. Chem. Int. Ed. Engl., 1996, 35, No. 23/24, 2801-2803).
Before epothilones can be used to treat diseases in patients, however, they must be formulated into a pharmaceutical composition that can be administered to the patient; for example, into a dosage form suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), or transdermal administration.
Certain epothilones and analogs thereof having advantageous activity are represented by formula I:
wherein the various symbols are as defined below. These and other epothilone analogs are further described, for example, in U.S. Pat. Nos. 6,605,599, 6,262,094, 6,288,237 B1, 6,613,912, and U.S. patent application Ser. Nos. 09/836,134 and 10/602,770, each of which is assigned to the present assignee and incorporated herein by reference in its entirety.
While these and other epothilone analogs possess significant therapeutic properties, they also present challenges to those skilled in the art of pharmaceutical compounding as a result of certain chemical properties. For example, certain epothilones and/or analogs thereof are susceptible to acid-catalyzed hydrolysis and thus, can rapidly degrade at low pH. In accordance with the present invention, a process and formulation have been found whereby epothilones and analogs thereof can be administered to a patient while achieving enhanced pH control of the formulation and thus, enhanced stability of the epothilones and analogs thereof. In one embodiment, the invention comprises a formulation for intravenous injection using cost-effective and readily-available infusion fluids such as saline and/or dextrose. Other formulations for administration of epothilones and epothilone analogs are described in U.S. patent application Ser. No. 10/051,727 filed Jan. 17, 2002, 10/055,653, filed Jan. 23, 2002, and Ser. No. 10/404,324, filed Apr. 1, 2003, each of which is assigned to the present assignee, and each of which is incorporated herein by reference in its entirety.